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https://hdl.handle.net/11000/30649
Potential Drugs Targeting Early Innate Immune Evasion of SARS-Coronavirus 2 via 2’-O-Methylation of Viral RNA
Title: Potential Drugs Targeting Early Innate Immune Evasion of SARS-Coronavirus 2 via 2’-O-Methylation of Viral RNA |
Authors: Encinar, José Antonio ![](/image/ORCID.jpg) MENÉNDEZ MENÉNDEZ, JAVIER ABEL ![](/image/ORCID.jpg) |
Editor: MDPI |
Department: Departamentos de la UMH::Bioquímica y Biología Molecular |
Issue Date: 2020-05-08 |
URI: https://hdl.handle.net/11000/30649 |
Abstract:
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causing the COVID-19
respiratory disease pandemic utilizes unique 20-O-methyltransferase (20-O-MTase) capping machinery
to camouflage its RNA from innate immune recognition. The nsp16 catalytic subunit of the
20-O-MTase is unusual in its requirement for a stimulatory subunit (nsp10) to catalyze the ribose
20-O-methylation of the viral RNA cap. Here we provide a computational basis for drug repositioning
or de novo drug development based on three di erential traits of the intermolecular interactions of
the SARS-CoV-2-specific nsp16/nsp10 heterodimer, namely: (1) the S-adenosyl-l-methionine-binding
pocket of nsp16, (2) the unique “activating surface” between nsp16 and nsp10, and (3) the RNA-binding
groove of nsp16. We employed 9000 U.S. Food and Drug Administration (FDA)-approved
investigational and experimental drugs from the DrugBank repository for docking virtual screening.
After molecular dynamics calculations of the stability of the binding modes of high-scoring
nsp16/nsp10–drug complexes, we considered their pharmacological overlapping with functional
modules of the virus–host interactome that is relevant to the viral lifecycle, and to the clinical features
of COVID-19. Some of the predicted drugs (e.g., tegobuvir, sonidegib, siramesine, antrafenine,
bemcentinib, itacitinib, or phthalocyanine) might be suitable for repurposing to pharmacologically
reactivate innate immune restriction and antagonism of SARS-CoV-2 RNAs lacking 20-O-methylation.
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Keywords/Subjects: COVID-19 drug repurposing methylation methyltransferases computational screening molecular docking molecular dynamics |
Knowledge area: CDU: Ciencias puras y naturales: Biología: Bioquímica. Biología molecular. Biofísica |
Type of document: application/pdf |
Access rights: info:eu-repo/semantics/openAccess Attribution-NonCommercial-NoDerivatives 4.0 Internacional |
DOI: https://doi.org/10.3390/v12050525 |
Appears in Collections: Artículos Bioquímica y Biología Molecular
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